Identification of a Novel, Potent, and Orally Bioavailable Guanidine-Based SHP2 Allosteric Inhibitor from Virtual Screening and Rational Structural Optimization for the Treatment of KRAS Mutant Cancers.

Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is a highly attractive therapeutic target for treating Kirsten rat sarcoma viral oncogene (KRAS) mutant cancers. In this work, a series of guanidine-based SHP2 allosteric inhibitors were discovered via virtual screening and rational structural optimization. Notably, lead compound 23 with potent SHP2 inhibitory activity (IC50 = 17.7 nM) effectively inhibited the proliferation, migration, and invasion of MIA PaCa-2 pancreatic cancer cells. Furthermore, compound 23 featured great in vivo pharmacokinetic properties (AUCpo = 4320 nM·h; F = 66.3%) and exhibited significant antitumor efficacy in the MIA PaCa-2 xenograft mouse model. This demonstrates that compound 23 is a potential lead compound for the development of SHP2 allosteric inhibitors to treat KRAS mutant cancers. Moreover, these guanidine-based scaffolds may provide an opportunity to mitigate the potential safety risks of the alkyl amine motif predominately incorporated in current SHP2 allosteric inhibitors.

Discovery of a Novel Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2) and Cyclin-Dependent Kinase 4 (CDK4) Dual Inhibitor for the Treatment of Triple-Negative Breast Cancer.

The treatment of triple-negative breast cancer (TNBC) remains a huge clinical challenge and dual-targeted small-molecule drugs might provide new therapeutic options for this type of breast cancer. In this work, we discovered a series of SHP2 and CDK4 dual inhibitors through a fused pharmacophore strategy and structural optimization. Notably, lead compound 10 with excellent SHP2 (IC50 = 4.3 nM) and CDK4 (IC50 = 18.2 nM) inhibitory activities effectively induced G0/G1 arrest to prevent the proliferation of TNBC cell lines. Furthermore, compound 10 showed great in vivo pharmacokinetic properties (F = 45.8%) and exerted significant antitumor efficacy in the EMT6 syngeneic mouse model. Western blotting and immunohistochemical analysis confirmed that 10 effectively targeted on both SHP2 and CDK4 and activated the immune response in tumors. These results indicate that lead compound 10, as the first SHP2 and CDK4 dual inhibitor, merits further development for treating TNBC.

Design, synthesis, and evaluation of novel pyridone derivatives as potent BRD4 inhibitors for the potential treatment of prostate cancer.

Since androgen receptor (AR) can bind to BRD4 protein and this binding can be blocked by BRD4 inhibitors, targeting BRD4 has emerged as a promising approach for the treatment of prostate cancer (PC). Herein, we designed and synthesized a series of 5-(1-benzyl-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one derivatives as novel BRD4 inhibitors for prostate cancer. Among them, compound 13 displayed the most robust BRD4 inhibitory activity with an IC50 value of 18 nM. Furthermore, 13 showed potent anti-proliferative activity against enzalutamide-resistant 22RV1 cells. The mechanism of action studies demonstrated that 13 induced cell apoptosis by regulating Bcl-2/Bax proteins and activating caspase-3 signaling pathway. In addition, the c-Myc level was significantly reduced in 22RV1 cells on the western blot assay. These findings collectively suggested that compound 13 might find potential use for the treatment of prostate cancer.